Nose-to-brain delivery of orexin-A - a novel therapy for narcolepsy.

Narcolepsy is a chronic sleep disorder caused by loss of nerve cells in the brain producing an important neurotransmitter, orexin-A (also called hypocretin-1). Narcolepsy patients experience frightening nocturnal hallucinations and abnormal need for sleep during the day with sudden episodes of paralysis (cataplexy) triggered by emotions such as laughter and anger. Narcolepsy is a relatively rare disease, but following the vaccination campaign in Norway for swine-flu in 2009/10, it is observed a multiplication of the number of cases in vaccinated children and adolescents compared with their peers who did not receive the vaccine. Available drugs have limited efficacy and many side effects. Replacement of the neurotransmitter orexin-A is considered to be the optimal treatment for this condition. The brain is a delicate organ and well-protected by a barrier (blood-brain barrier) that prevents most substances from penetrating into the brain. The close connection between the brain and the nose via the olfactory nerve, however, constitutes a potential way to circumvent the blood-brain barrier and thus a way to replace orexin-A deficiency in narcolepsy patients. OptiNose AS has developed new and patented devices for enhanced delivery of drugs to the nose that have shown excellent results in clinical trials. A special variant of the device optimized for nose-to-brain delivery will be used in this project. Hovione FarmaCiencia SA, Portugal will develop and produce orexin-A powder formulation. The sleep studies will be conducted at the National Centre for Neurodevelopmental Disorders and Hypersomnias (NevSom), University of Oslo. Smerud Medical Research International AS will oversee the planning, implementation and analysis of clinical trials and ensure that they meet the regulatory requirements necessary for marketing authorisation of a new and better treatment for narcolepsy with great commercial potential. The biggest challenge for the project is the formulation work that has taken more time than anticipated. The problem issues have been identified and mitigation solutions are evaluated.it has not been possible to resolve formulation issues at the current timeline.

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The aim is to develop an intranasal dry powder orexin-A formulation for the treatment of narcolepsy, a chronic sleep disorder caused by loss of nerve cells in the brain producing an important neurotransmitter orexin-A (also called hypocretin-1).Narcolepsy is a relatively rare disease, but following the vaccination campaign in Norway for swine-flu in 2009/10, it is observed a multiplication of the number of cases in vaccinated children and adolescents compared with their peers who did not receive the vaccine. Available drugs have limited efficacy and many side effects. Replacement of the neurotransmitter orexin-A is considered to be the optimal treatment for this condition. OptiNose has developed a new Breath Powered device technology for enhanced drug delivery into the brain along cranial nerve fibers innervating the upper part of the nose. This direct nose-to-brain circumvents the blood-brain barrier to offer better therapy also for other neurological and psychiatric disorders with great unmet needs. The innovative Breath Powered Bi-Directional nasal delivery system combined with a new dry powder formulation of orexin-A constitute the two underlying technological concepts in this proposal, whereas efficaciously treating narcolepsy with orexin-A is the third innovation. Partners include Hovione FarmaCiencia SA, Portugal; the National Centre for Neurodevelopmental Disorders and Hypersomnias (NevSom), University of Oslo and Smerud Medical Research International, Oslo, Norway. Work packages follow state-of-the-art methodology for drug development: drug formulation work, pharmacology and safety studies in rats and healthy volunteers, as well as two clinical proof-of-concept trials in patients. The unmet therapeutic need, clear clinical endpoints and orphan status of narcolepsy make the OptiNose N2B orexin-A substitution an attractive product opportunity with high commercial potential and probability of success.